The present invention relates to the use of certain benzoic acid derivatives which act as peroxisome proliferator activated receptor (PPAR) agonists, in particular gamma receptors (PPARxcex3), and so are useful in the treatment of states of insulin resistance, including type 2 diabetes mellitus. Novel pharmaceutical compositions and novel compounds are also defined, together with methods of their production.
Traditionally, therapeutic intervention in type 2 diabetes has had a xe2x80x98glucocentric focusxe2x80x99 dominated by the use of insulin secretogogues e.g. the sulphonylureas and the measurement of glycated haemoglobin (HbA1c) or fasting blood sugar level (FPG) as indices of diabetic control. In the USA, patients with type 2 diabetes are usually treated with diet and, when needed, a sulphonylurea compound. However, it is estimated that approximately 30% of patients initially treated with sulphonylurea agents have a poor response and in the remaining 70%, the subsequent failure rate is approximately 45% per annum. Other estimates put failure rates higher with few patients responding after 10 years therapy. A treatment-related increase in body weight is also experienced with these agents. Prior to the FDA approval of metformin in 1995, the only therapeutic option for type 2 diabetic patients, in whom sulphonylurea therapy had failed, was insulin.
Despite the introduction of newer agents both the incidence and prevalence of type 2 diabetes continues to increase on a global basis. Approximately 16 million people in the USA have diabetes mellitus, 90-95% of whom have type 2 disease. This represents an enormous healthcare burden; estimated in 1998 to be some $98 billion per annum in direct and indirect healthcare costs. Recently, both the ADA and WHO have revised guidelines for the diagnosis of diabetes and classified diabetes more according to aetiology. The threshold for diagnosis (FPG greater than 126 mg/dl) has been lowered and the term xe2x80x98type 2xe2x80x99 is now used to describe mature onset diabetics who have not progressed to insulin therapy. After the ADA implemented these new criteria in 1997, the prevalence of the type 2 disease sector increased by nearly 6 million people in the seven major pharmaceutical markets (France, Germany, Italy, Japan, Spain, UK and USA).
Apart from often mild acute symptoms, type 2 diabetics are also at a considerable risk of developing long term complications of the disease. These include a 4-5 fold higher risk, (compared with non-diabetics), of developing macrovasular disease including CHD and PVD and microvascular complications including retinopathy, nephropathy and neuropathy. In many individuals, overt type 2 diabetes is preceded by a period of reduced insulin sensitivity (insulin resistance), accompanied by a cluster of other cardiovascular risk factors, collectively termed as insulin resistance syndrome (IRS).
It has been estimated that approximately 80% of type 2 diabetics are obese and other co-morbidities of the IRS include: dyslipidemia, hyperinsulineria, raised arterial blood pressure, uricemia and a reduced fibrinolysis. Given the increased global prevalence and incidence of type 2 diabetes and the very high costs of treating the long term complications of the disease there is tremendous interest in the development of agents that delay or prevent the onset of type 2 diabetes and in those that reduce the risk of cardiovascular complications associated with IRS. These activities have lead to the introduction of the thiazolidinedione (TZD) class of insulin sensitisers that improved the dyslipidemia and thus restored the insulin sensitivity leading to improved glycemic control and lower HbA1c levels.
Although the complex interplay between lipids and carbohydrates as metabolic fuels has been recognised for many decades it is only recently, that researchers and clinicians have begun to focus on the importance of dyslipidemia seen in type 2 diabetes. Much has been made of the relative sensitivities of muscle, liver and adipose tissues to insulin and a case for the primacy of insulin resistance in adipose tissue leading to the IRS has been debated. A typical dyslipidemic atherogenic lipoprotein phenotype (referred to as type B) is seen in IRS including frequently in type 2 diabetics, characterised by a modestly raised LDL-C, a more significant increase in VLDL-TG and reduced HDL. Apparently, changes in the physicochemical properties of VLDL-TG particles result in slower plasma clearance rates and in the generation of small dense LDL particles. The latter permeate the vascular endothelium more readily and are more prone to oxidation and glyration and are considered to play a critical role in atherogenesis in large vessels. Although more difficult to measure, improved free fatty acid (IFFA) flux is increasingly considered to play an important role in the IRS affecting metabolic events in muscle, liver, adipose tissue and pancreas.
The first generation TZDs e.g. troglitazone, pioglitazone, rosiglitazone were in clinical development before the putative mechanism of action was discovered and published in 1995 (PPARxcex3 activation). It is clear from experience with these first generation agents that it is difficult to predict from animal pharmacology the safety and efficacy profile these agents will have in the clinic. Thus, knowledge of the putative mechanism of action of this class coupled with concerns regarding safety, offers the opportunity to identify non-TZD activators of PPAR for the treatment of type 2 diabetes and is the subject of this invention. Furthermore, we recognise that agents with a dual action at both xcex1 and g PPAR may have additional benefits in reducing diabetic co-morbidities, particularly raised triglycerides. Such agents may be useful in the treatment of type 2 diabetes, the IRS, dyslipidemia and in reducing risk of cardiovascular disease.
Certain heterocyclic amides and their use as leukotriene antagonists is described in EP-A-179619. Additional phenyltetrazole leukotriene D4 receptor antagonists have been described by Sawyer et al., J. Med. Chem. 1992, 35, 7, 1200-1209.
The present invention provides the use of a compound of formula (I) 
or a pharmaceutically acceptable salt or ester thereof, in the preparation of a medicament for use in the activation of PPAR,
where Q, X, Y and Z are either xe2x80x94CRaxe2x95x90, xe2x80x94CRbxe2x95x90CRcxe2x80x94 or xe2x80x94Nxe2x95x90; where Ra, Rb and Rc are independently selected from hydrogen, halo or a bond, such that together with the nitrogen atom to which Y and Z are attached, they form a five or six-membered aromatic ring;
R1 and R3 are independently selected from C1-3alkyl, halo, haloC1-3alkyl, C1-3alkoxy, or haloC1-3alkoxy;
n and m are independently selected from 0, 1 or 2;
A is an alkylene, alkenylene or alkynylene chain optionally interposed by a heteroatom; and
R2 is an optionally substituted aryl, optionally substituted heterocyclyl or optionally substituted cycloalkyl moiety.
As used herein, the term xe2x80x9chydrocarbylxe2x80x9d refers to alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl groups.
As used herein the term xe2x80x9cheterocyclylxe2x80x9d refers to single or fused ring structures which, unless stated otherwise, may be aromatic or non-aromatic in nature and which suitably contain from 2 to 20 ring atoms, suitably from 5 to 8 ring atoms, at least one of which and suitably up to four of which are heteroatoms. The term xe2x80x9cheteroatomxe2x80x9d includes oxygen, sulphur and nitrogen. Where a heteroatom is nitrogen, it will be further substituted for example by hydrogen or an alkyl group.
In this specification the term xe2x80x9carylxe2x80x9d refers to phenyl, biphenyl and naphthyl.
The term xe2x80x9cheterocyclylxe2x80x9d includes aromatic or non-aromatic rings, for example containing from 4 to 20, Examples of such groups include furyl, thienyl, pyrrolyl, pyrrolidinyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, benzothienyl or benzofuryl.
xe2x80x9cHeteroarylxe2x80x9d refers to those groups described above which have an aromatic character.
In this specification the term xe2x80x9calkylxe2x80x9d when used either alone or as a suffix includes straight chain or branched structures. These groups may contain up to 10, preferably up to 6 and more preferably up to 4 carbon atoms. Similarly the terms xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d refer to unsaturated straight or branched structures containing for example from 2 to 10, preferably from 2 to 6 carbon atoms. Cyclic moieties such as cycloalkyl, cycloalkenyl and cycloalkynyl are similar in nature but have at least 3 carbon atoms, suitably from 3 to 20 carbon atoms and preferably from 3 to 7 carbon atoms. Terms such as xe2x80x9calkoxyxe2x80x9d comprise alkyl groups as is understood in the art.
The term xe2x80x9chaloxe2x80x9d includes fluoro, chloro, bromo and iodo. References to aryl groups include aromatic carbocylic groups such as phenyl and naphthyl.
Preferably, the group comprising xe2x80x94Yxe2x80x94Xxe2x80x94Qxe2x80x94Zxe2x80x94 and the nitrogen to which it is attached forms a 5-membered aromatic ring. Preferably however, any other heteroatoms in this ring are also nitrogen. Examples of such groups include tetrazolyl, triazolyl, pyrazolyl, imidazolyl pyrrolyl, pyridyl, pyridazinyl or pyrimidinyl, and preferably tetrazolyl, pyrazolyl or imidazolyl.
Thus examples of the group formed by xe2x80x94Yxe2x80x94Xxe2x80x94Qxe2x80x94Z and the nitrogen atom to which they are attached include the following groups (i) to (vii); 
where Rd and Rc are independently selected from hydrogen or halo, preferably hydrogen, * indicates the nitrogen atom illustrated in formula (I) and + indicates the point of attachment to he group xe2x80x94Axe2x80x94R2.
Suitable optional substituents for the group R2 include alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxy, aralkyl, cycloalkyl, cycloalkenyl cycloalkynyl, halo, cyano, nitro, C(O)aR8, OR8, S(O)bR8, NR9R10, C(O)NR9R10, OC(O)NR9R10, NR8C(O)aR9, NR8CONR9R10, Nxe2x95x90CR9R10, S(O)bNR9R10 or NR8S(O)bR10 where R8, R9 and R10 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxy, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl, any of which may themselves be optionally substituted, a is 1 or 2 and b is 0, 1, 2 or 3.
Suitable optional substituents for alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxy, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl groups R8, R9 and R10 include halo, nitro cyano, alkanoyl such as acetyl, oxo, carboxy or salts or esters thereof; alkoxy such as methoxy, ethoxy or propoxy, aryloxy such as phenoxy, thioalkyl such as thiomethyl, thioethyl or thiopropyl, sulphate, haloalkyl such as tifluoromethyl, aryl such as phenyl, carbamate, amino, mono- or di-alkyl amino such as methylamino or di-methylamino. Aryl, heterocyclyl or aralkyl groups R8, R9 and R10 may further be substituted by alkyl, alkenyl or alkynyl groups suitably having from 1 to 4 carbon atoms.
In particular R2 is an optionally substituted heterocyclic group, such as pyridyl, indole, quinoline, isoquinoline, benzimidazoline, benzpyrazole.
Preferred optional substituents for such groups include alkyl, aryl and groups of formula NR8C(O)aR9 where R8, R9 and a are as defined above.
Where R2 is substituted by a group NR8C(O)nR9, R8 is preferably hydrogen, whilst R9 is preferably alkyl, such as C1-6 alkyl, or cycloalkyl, such as cyclopentyl.
Suitably R3 is alkoxy in particular methoxy or halo such as bromo. Preferably m is 0 or 1.
Suitable groups for A include xe2x80x94(CH2)pxe2x80x94, xe2x80x94O(CH2)pxe2x80x94, xe2x80x94(CH2)pOxe2x80x94 xe2x80x94(CH2)pxe2x80x94, xe2x80x94NR5(CH2)pxe2x80x94 or xe2x80x94(CH2)pNR5xe2x80x94 where p is an integer of 1 to 3 and is preferably 1 and R5 is hydrogen or alkyl, in particular C1-6 alkyl such as methyl.
Preferably l is 1.
Preferably n is 0 or 1. Ideally n is 0.
Preferably m is 0 or 1. Ideally m is 0.
Preferably R1 is selected from C1-3alkyl, halo, haloC1-3alkyl and C1-3alkoxy.
In the compounds of formula (I), the carboxylic acid group is suitably at the ortho position on the benzyl ring. Thus preferred compounds of formula (I) are compounds of formula (II) 
where X, Y, Z, Q, A, R1, R2, R3, m and n are as defined in relation to formula (I).
Furthermore, in compounds of formula (I), the group R2xe2x80x94Axe2x80x94 is suitably in the para position relative to the ring formed by the Yxe2x80x94Xxe2x80x94Qxe2x80x94Zxe2x80x94 and the nitrogen atom to which they are attached. Thus further preferred compounds of formula (I) are compounds of formula (III) 
where X, Y, Z, Q, A, R1, R2, R3, m and n are as defined in relation to formula (I).
Particular examples of compounds of formula (I) include the compounds listed in Table 1 and esters thereof.
The use of certain compounds of formula (I) in any medical application has not been described before. Hence, in a further aspect the invention provides the use of these particular compounds as medicaments, and pharmaceutical compositions containing them.
Thus the invention provides a compound of formula (IA) which comprises a compound of formula (I) as defined above, provided that
(a) where Q, X, Y and Z together with the nitrogen atom to which they are attached from a group of formula (i) above, when the group R2xe2x80x94Axe2x80x94 is attached at the meta position on the phenylene ring, and A is ethylene, xe2x80x94O(CH2)xe2x80x94 or xe2x80x94(CH2)Sxe2x80x94, R2 is other than quinoline optionally substituted by chloro, or unsubstituted benzothiazol; or
(b) where Q, X, Y and Z together with the nitrogen atom to which they are attached from a group of formula (i) above, when R3 is methoxy, m is 1, the group R2xe2x80x94Axe2x80x94 is attached at the para position on the phenylene ring, and A is xe2x80x94(CH2)xe2x80x94, R2 is other than indole substituted by xe2x80x94NR8C(O)2R9 where R8 is hydrogen and R9 is alkyl; or for use a medicament.
Suitable compounds of formula (IA) are compounds where Q, X, Y and Z together with the nitrogen atom to which they are attached form a group heterocyclic group other than tetrazole.
In addition, the invention provides a pharmaceutical composition comprising a compound of formula (IA) in combination with a pharmaceutically acceptable carrier.
Preferred groups within formula (IA) are as set out above in relation to formula (I).
Compounds of formula (IA) are novel and these form a further aspect of the invention.
Compounds of formula (I) are either known compounds or they may be prepared using conventional methods. For example, benzoic acid, 2-[[5-[3-(2-quinolinylmethoxy)phenyl]-2H-tetrazol-2-yl]methyl]-(9CI) (Compound 37 in Table 1) and its preparation is described by Sawyer, J. Scott; Baldwin, Ronald F.; Rinkema, Lynn E.; Roman, Carlos R.; Fleisch, Jerome H. Optimization of the quinoline and substituted benzyl moieties of a series of phenyltetrazole leukotriene D4 receptor antagonists. J. Med. Chem. (1992), 35(7), 1200-9. CODEN: JMCMAR; ISSN: 0022-2623. CAN 116:174064 CAPLUS.
In particular however, compounds of formula (I) may be prepared by reacting a compound of formula (IV) 
where X, Y, Z, Q, A, R1, m and n are as defined in relation to formula (I); R20 completes an ester group, and so is, for example an alkyl group, R21 is a leaving group; with a compound of formula (V)
R2xe2x80x94Hxe2x80x83xe2x80x83(V)
where R2 is as defined in relation to formula (I) or a precursor thereof, and thereafter, if desired, removing the group R20 to form the corresponding carboxylic acid.
The reaction is suitably effected in an organic solvent such as dimethylformamide (DMF) in the presence of a base such as an alkali metal carbonate such as potassium carbonate. Suitable leaving groups for R21 include halo such as bromo, mesylate and tosylate.
Any de-esterification is suitably carried out by addition of a base such as an alkali metal hydroxide such as lithium hydroxide or sodium hydroxide in the presence of an organic solvent such as an alcohol for instance, methanol, or trifluoroacetic acid (TFA).
Compounds of formula (IV) are suitably prepared by reacting a compound of formula (VI) 
where X, Y, Z, Q, A, R1, R3 m and n are as defined in relation to formula (I) and R20 is as defined in relation to formula (V) above, with an appropriate leaving group reagent. For example, where R21 is a halogen group, the compound will be reacted with a halogenating agent such as N-bromosuccinimide in the presence of a base such as azoisobutyronitrile (AIBN).
Compounds of formula (VI) where A includes for example heteroatoms spaced from the ring such as nitrogen, may be prepared by reacting a compound of formula (VIA) 
where R25 is an alkyl group substituted by a leaving group, with an appropriate primary or secondary amine in particular a monoalkylamine such as methylamine. Suitable leaving group substituents for R25 include those listed above for R21. The reaction is suitably effected in an organic solvent such as an alcohol like ethanol at moderate or depressed temperatures, for example of from xe2x88x9220xc2x0 C. to ambient temperature, and conveniently at about 0xc2x0 C.
Compounds of formula (VI) are suitably prepared by reacting a compound of formula (VII) 
where X, Y, Z, Q, A, R3 and n are as defined in relation to formula (I); with a compound of formula (VIII) 
where R1 and n are as defined in relation to formula (I), R20 is as defined in relation to formula (VI) and R22 is a leaving group such as halo, and in particular bromo. The reaction is suitably effected in an organic solvent such as acetone or DMF, in the presence of a base such as an alkali metal carbonate for instance potassium carbonate.
Compounds of formula (VII) will be prepared using various methods depending upon the precise nature of the heterocyclic ring completed by xe2x80x94Yxe2x80x94Xxe2x80x94Qxe2x80x94Zxe2x80x94. These methods would be apparent to the chemist and can be based upon literature references. For example, where xe2x80x94Yxe2x80x94Xxe2x80x94Qxe2x80x94Zxe2x80x94 together with the nitrogen atom to which they are attached form a tetrazole ring, these may be prepared by reacting a compound of formula (IX) 
where R3, m and A are as defined in relation to formula (I), with an azide such as sodium azide or n-tributyltin azide (n-Bu3SnN3). The reaction may be effected in a solvent such as N-methylpyrrolidine (NMP) in the presence of abase such as triethylamine hydrochloride where necessary.
Such a reaction will result in the production of a compound of formula (X) 
where R3, m and A are as defined in relation to formula (I). This may be converted to other compounds of formula (VII) such as pyrazoles by heating the compound with an alkene of formula (XI) 
in the presence of a condensation reagent such as Hg(OAc)2, and thereafter rearranging the product of formula (XII) 
where R3, m and A are as defined in relation to formula (I) for example by heating to temperatures of from 150 to 200xc2x0 C., in the presence of dichlorobenzene (DCB) to yield the corresponding pyrazole of formula (XIII) 
Alternatively, pyrazoles can be prepared by reacting a compound of formula Compounds of formula (VIII) and (IX) are either known compounds of they can be prepared from known compounds using conventional methods.
Alternatively, compounds of formula (I) may be prepared by reacting a compound of formula (XIV) 
where X, Y, Z, Q, A, R2, R3, m and n are as defined in relation to formula (I); with a compound of formula (VIII) as defined above. The reaction is suitably effected under conditions similar to those described for the reaction between compounds of formula (VII) and (VIII).
Compounds of formula (XIV) may be prepared by treating a compound of formula (XV) 
where R2, R3, A and m are as defined in relation to formula (I) in a similar manner and with similar reagents to that described above in relation to the compounds of formula (IX).
In yet a further alternative, compounds of formula (I) where A contains a nitrogen heteroatom may be prepared by reduction of the corresponding amide. Thus for example, compounds of formula (I) where A is a group xe2x80x94NR26CH2xe2x80x94 where R26 is hydrogen or alkyl may be prepared by reduction of a compound of formula (XVI) 
where X, Y, Q, Z, R1, R2, R3, m and n are as defined in relation to formula (I), R20 is as defined in relation to formula (IV) and R26 is hydrogen or alkyl such as methyl, and thereafter, if necessary or desired, removing any protecting groups R20 for example by deesterification. Suitably the reaction is effected using a reducing agent such as trichlorosilane in an organic solvent such as dichloromethane. Elevated temperatures, conveniently the reflux temperature of the solvent are suitably employed. Optionally the reaction is effected in an inert atmosphere, for example in an argon atmosphere. Compounds of formula (XVI) are suitably prepared by reacting a compound of formula (XVII) 
where X, Y, Q, Z, R2, R3 and m are as defined in relation to formula (I), R26 is as defined in relation to formula (XVI) with a compound of formula (VIII) as defined above, under conditions similar to those described for the reaction between compounds of formula (VII) and (VIII).
Compounds of formula (XVII) may be obtained by treatment of a compound of formula (XVIII) 
where R2, R3 and m are as defined in relation to formula (I) and R26 is as defined in relation to formula (XVI) as described above for the treatment of compounds of formula (IX).
Compounds of formula (XVIII) are suitable prepared by reacting a compound of formula (XIX) 
where R3 and m are as defined above, with an amine of formula (XX) 
where R2 and R26 are as defined above, using conditions which would be well known in the art.
Where A contains an oxygen atom directly bonded to the phenyl ring, compounds may be prepared by derivatisation of the corresponding hydroxy compound. Thus compounds of formula (XXI) 
where X, Y, Q, Z, R2, R3, n and m are as defined in relation to formula (I), R20 is as defined in relation to formula (V), with a compound of formula (XXII)
R27xe2x80x94R28xe2x80x83xe2x80x83(XXII)
where R27 is a group such that xe2x80x94OR27 is a group xe2x80x94Axe2x80x94R2 as defined in relation to formula (I) or a precursor thereof, and R28 is a leaving group such as halogen, mesylate or tosylate. Reaction conditions are suitably similar to those described above in relation to the reaction of compounds of formula (IV) and (V).
Compounds of formula (XIX) and (XX) are known compounds or they can be prepared from known compounds by conventional methods.
In yet a further alternative method, the compounds of the invention may be prepared by reacting a compound of formula (XXIII) 
where X, Y, Q, Z, R1 and n are as defined in relation to formula (I), R20 is as defined in relation to formula (V) and R29 is a leaving group, with a compound of formula (XXIV) 
where R2, R3, A and m are as defined in relation to formula (I) and R30 is a boronate derivative, 
for example of formula xe2x80x94B(OH)2 or ; and thereafter if desired or necessary removing any protecting group R20. Suitable leaving groups for R29 include halogen such as iodine. The reaction is suitably effected under an inert atmosphere for example of argon in an organic solvent such as dimethyl formamide in the presence of a palladium catalyst such as palladium chloride. The reaction is suitably effected at moderated temperatures, for example from 20-100xc2x0 C., suitably at about 60xc2x0 C.
Compounds of formula (XXIII) may be prepared by reacting a compound of formula (XXV) 
where X, Y, Q and Z are as defined in relation to formula (I) and R29 is as defined in relation to formula (XXIII) with a compound of formula (VIII) as defined above. Reaction conditions are suitably similar to those described in relation to the reaction between compounds of formula (VII) and (VIII).
Compounds of formula (XXIV) are suitably prepared by reacting a compound of formula (XXVI) 
wherein R2, R3, A and m are as defined in relation to formula (I) and R31 is a halogen group such as iodine, with appropriate diboron compound as illustrated hereinafter.
Compounds of formula (XXV) and (XXVI) are either known compounds or they can be prepared from known compounds by conventional methods.
The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal track, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil or a mineral oil such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring and preservative agents.
Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.
Topical formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedure well known in the art.
Compositions for administration by insufflation may be in the form of a finely divided. powder containing particles of average diameter of, for example, 30xcexc or much less, the powder itself comprising either active ingredient alone or diluted with one or more physiologically acceptable carriers such as lactose. The powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50 mg of active ingredient for use with a turbo-inhaler device, such as is used for insufflation of the known agent sodium cromoglycate.
Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
For further information on Formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. In particular, compounds of formula (I) and compositions containing them will be used in the treatment of diabetes.
Thus in yet a further aspect, the invention provides a method of treating diabetes which comprises administering to a patient an effective amount of a compound of formula (I) as defined above.